DESCRIPTION: (Verbatim from the Applicant's Abstract) Ginsenoside Rg3, Cynandione A, and p-methoxy-trans-cinnamic acid (MCA), all isolated from Oriental herbal medicines, attenate neurotoxicity induced by glutamate in vitro. Neoline, isolated from Aconiti tubers, protects short-term memory, possibly by influencing central cholinergic transmission. The present proposal is designed to elucidate the mechanisms of their neuroprotective activities in vitro as well as in vivo. The latter mandates transport of these agents across the blood-brain barrier (BBB). Thus, prodrug approaches are adopted for brain delivery. Specfic Aim 1 tests a hypothesis that Rg3 and MCA exet neuroprotective activities by inhibiting Ca ++ influx by determining their efects on Ca++ influx in vitro. Aim 2 tests the hypothesis that Rg3, cynandione A and MCA exert neruoprotective activity by inhibiting neuronal apoptosis by assessing their effects on apoptosis and its markers in vitro and in vitro. Aim 3 tests a hypothesis that neoline ameliorates deficits in short-term memory by influencing central cholinergic transmission in the brain. As such, we will determine its effects on muscarinic receptors in vitro and in vivo as, and Ach levels in vivo. Aim 4 addresses issues involved in drug delivery across the BBB. To this end, we propose to synthesize a series of ester prodrugs of Rg3, and Rg3 analog (protopanaxadiol), and MCA. Aim 5 concerns with development of injectable formulations for these test compounds. Note that they are all water-insoluble. The overall goal of this proposal is to identify novel strategies of blocking oxidative stress, which is the primary cause of neuronal death or memory impairment linked to neurodegeneration. Results of this three-way collaborative research are significant in that: I) these curative s have been used in Asian societies for centuries; ii) no effective treatments are currently available for such adult neurodegenerative disorders as Alzheimer's disease or for injuries to the CNS/stroke; and iii) the progressive memory loss observed in various dementia is extremely debilitating, making any palliative measure a major clinical development.